Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional modification highly enriched in the mammalian central nervous system. Mediated by adenosine deaminase acting on RNA (ADAR) enzymes, this process alters amino acid sequences, influences splice-site selection, regulates RNA stability and innate immune tolerance to cellular RNAs. A-to-I editing resulting in protein recoding by ADAR2 has a demonstrated essential role in modulating neurotransmitter receptor function, synaptic plasticity, and higher-order cognitive processes. However, the distinct behavioural and cognitive contributions of individual ADAR enzymes, ADAR1 and ADAR2, has not been previously possible to evaluate in adult mice due to embryonic lethality of the ADAR1 deficient mice. Here we have investigated the requirement of ADAR1, as well as the combined role of ADAR1 and ADAR2, in maintaining baseline behavioural phenotypes and cognitive function.
We evaluated Adar1-editing deficient and Adar1/Adar2 double-deficient mouse models alongside control littermates. We subjected adult cohorts of both male and female mice to a comprehensive suite of behavioural assays. These tests assessed baseline locomotion, anxiety-like behaviours, motor co-ordination, and cognitive performance, including spatial learning and memory recognition. Standardised behavioural phenotyping revealed no significant differences between the ADAR1 editing deficient mice and controls. The loss of ADAR1 mediated editing alone, or the complete absence of A-to-I editing in the double mutant model, did not alter locomotor activity, anxiety-like profiles, or memory retention. Crucially, this lack of behavioural divergence was consistent across both male and female cohorts, indicating no sex-dependent phenotypes in the tested paradigms.
Although A-to-I RNA editing is a vital molecular mechanism in the brain for recoding and tuning neurotransmitter responses, Adar1-editing deficient and Adar1/Adar2 double deficiency do not cause overt behavioural or cognitive impairments under standard testing conditions. Our study does not exclude that A-to-I RNA editing deficient animals may have an abnormality in a behavioural endophenotype not measured in our current behavioural battery. These findings suggest that the behavioural impacts of these enzymes may be highly context-specific, subtle, or mitigated by complex developmental compensatory mechanisms.